Does the combination of buprenorphine/naltrexone have antidepressant efficacy in animal models?

Abstract

Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focused on the development of kappa opioid receptor (κ-receptor) antagonists. In this thesis I have tested the hypothesis that buprenorphine/naltrexone combination has antidepressant efficacy. Buprenorphine acts as a partial mu opioid receptor (μ-receptor) agonist and a κ-receptor antagonist. By combining buprenorphine with the non-selective opioid receptor antagonist naltrexone, the idea was that the activation of μ-receptors would be reduced and the κ-antagonist properties enhanced. First, the appropriate dose of the combination that would act as a short acting κ-receptor antagonist was investigated in the mouse-tail withdrawal test. A dose of BU10119, a novel compound derived from buprenorphine, with pharmacology resembling buprenorphine/naltrexone combination was also investigated. It was established that a combination dose of buprenorphine (1 mg/kg, i.p.) with naltrexone (1 mg/kg, i.p.) functioned as a short acting κ-antagonist in the mouse-tail withdrawal test and BU10119 (1 mg/kg, i.p.) is a к-antagonist with a rapid onset and a duration of action not more than 24 hours. Furthermore, these doses of the buprenorphine/naltrexone and BU10119 were neither rewarding nor aversive in the conditioned place preference paradigm, and were without significant locomotor effects. Systemic co-administration of buprenorphine/ naltrexone (1 mg/kg, i.p.) and BU10119 in adult CD-1 male mice produced an antidepressant-like response in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by either treatment. Moreover, pretreatment with buprenorphine/naltrexone and BU10119 blocked stress- induced analgesia in adult male CD1 mice. However, they were not capable of blocking restraint stress-induced elevation of corticosterone levels. Gene expression of k-receptor, prodynorphin and Corticotropin-Releasing Hormone Receptor 1 were not significantly altered by restraint stress or к-receptor antagonist treatment in prefrontal cortex, nucleus accumbens, hippocampus and amygdala. I propose that the combination of buprenorphine with naltrexone and BU10119, both represent a novel approaches to the treatment of depression.